Contractile dysfunction occurs in muscles of humans and animals with age. One of the most devastating dysfunctions is the loss of muscle strength, which can ultimately lead to disability and a loss of independence for elderly individuals. The loss of strength occurs gradually in men, but in women there is an increased rate of strength decline around the time of menopause. The mechanisms underlying this accelerated loss are not known but may to be related to ovarian hormone changes. Because the time courses and extent of age- and hormone-related contractile dysfunctions are not defined in female mice, a longitudinal assessment of strength is needed and is the focus of the first aim of this pilot project. We hypothesize that strength will decline as estradiol levels are reduced during menopause and as a result of ovariectomy. We also hypothesize that estradiol replacement following ovariectomy will reverse the strength loss. The goal of the second aim is to determine molecular mechanisms underlying estradiol-related strength losses. Based on preliminary data, the initial focus of these molecular mechanisms will be on the contractile protein, myosin. The central hypothesis to be tested is that reduced circulating estradiol causes declines in strength by detrimentally altering myosin structure and function. Myosin function will be assessed at the cellular and molecular levels and myosin structure will be determined by site-specific spin labeling and electron paramagnetic resonance spectroscopy. The long-term objective of our research is to elucidate the molecular mechanisms underlying age- and hormone- related strength losses and utilize this knowledge to devise strategies to prevent or reverse the dysfunction. [unreadable] [unreadable]